Field of the Invention
The present disclosure is generally directed to compositions and methods for treating diseases that are ameliorated by the inhibition of CYP26 mediated retinoic acid metabolism.
Description of Related Art
Retinoic acid (RA), the active metabolite of vitamin A, is an important endogenous signaling molecule regulating cell cycle and maintenance of epithelia. RA isomers are also used as drugs to treat various cancers and dermatological diseases. However, the therapeutic uses of RA isomers are limited due to side effects such as teratogenicity and resistance to treatment, emerging mainly from autoinduction of RA metabolism. To improve the therapeutic usefulness of retinoids, RA metabolism blocking agents (RAMBAs) have been developed. These inhibitors generally target the cytochrome P450 (CYP) enzymes because RA clearance is predominantly mediated by P450s. Since the initial identification of inhibitors of RA metabolism, CYP26 enzymes have been characterized as the main enzymes responsible for RA clearance.
The CYP26A1 and CYP26B1 enzymes appear to be the predominant all-trans-retinoic acid (atRA) hydroxylases in humans, both in the liver and in extrahepatic tissues. In cell culture, differential expression of CYP26A1 changes the cells susceptibility to apoptosis, presumably via different metabolic capacity of the cells. Similarly, inhibition of P450 mediated atRA metabolism makes the cells more susceptible to proapoptotic effects of atRA. In acute promyelocytic leukemia patients receiving atRA therapy, therapy resistance and relapse has been attributed to CYP26 induction and increased atRA elimination in cancer cells. Whether any of the known CYP26A1 inhibitors also inhibit CYP26B1 is currently unknown and the pharmacological effects of selective CYP26A1 versus CYP26B1 inhibition have not been characterized.